The pneumococcus remains the cause of meningitis with the greatest morbidity and mortality. Over the past 22 years of this application, we have sought to understand the biochemical basis of the inflammatory response to pneumococci in the subarachnoid space and to determine how pneumococci traffic across the blood brain barrier of cerebral microvessels. In the past application cycle, we discovered several overarching principles of central nervous system (CNS) infection: We determined how the pneumococcus localizes to the blood brain barrier (CbpA on the cell wall ligates laminin receptor LR) and then penetrates into the CNS (phosphorylcholine PCho on the cell wall ligates platelet activating factor receptor PAFr) and have shown that these steps are shared by other meningeal pathogens. We showed how neuronal cells die by apoptosis during meningitis and revealed the role of cell wall/TLR2 in host damage. The central hypothesis of this application is that critical bacterial cell wall/host cell ligand-receptor interactions play a dominant role in influencing the course and outcome of pneumococcal infection and that organ specific responses script how the lung recovers relatively unscathed from pneumonia while the brain is devastated by meningitis. An understanding of the driving factors for these differences,to be investigated in this application, represent both new aspects of bacterial pathogenesis and avenues of high potential for tangible medical impact. We propose in Aim 1 to determine the regulation of CbpA, the pneumococcal cell wall-bound adhesin for LR on the blood brain barrier. In Aim 2, we will map the PCho-PAFr response pathways in epithelia, endothelia, and neurons (adult and fetal) to determine the underlying mechanisms of differences in cell wall uptake and host cell fate. We will also determine the pathway by which PCho-PAFr drives neuronal apoptosis in adult neurons versus neuroregeneration in fetal neurons. Finally, in Aim 3, we have learned that interruption of the cell wall/TLR2 interaction protects against apoptotic organ injury but this is not sufficient to prevent mortality. Understanding of this dichotomy will tie cell fate decisions to TLR2 signaling and introduce pneumococcal manipulation of TGFss into pathogenesis. PUBLIC HEALTH RELEVANCE: Streptococcus pneumoniae, the leading cause of pneumonia, sepsis, and meningitis worldwide, is a model for determining the mechanisms of lethal inflammation and injury in the brain. We seek to define how the cell wall of pneumococcus drives bacterial trafficking in the host and causes tissue injury especially in the brain and heart. This information will direct efforts to develop neuroprotective treatments for infants and children.